There is increasing evidence that chronic sleep disorders in children with autism spectrum disorder (ASD), Angelman Syndrome (AS) and Smith-Magenis syndrome (SMS) are associated with disturbed melatonin secretion and melatonin administration has been shown to be effective in these populations. For children who have difficulties swallowing a tablet, Neurim has developed an age-appropriate Melatonin formulation in the form of mini-tablets which have the same dissolution profile as the Circadin® tablets product, thus should produce the same melatonin concentration-time profile with the same effects. This study concerns the pharmacokinetic study.

The purpose of this study is to :

Establish the 24 hour baseline profile of endogenous saliva melatonin concentrations and urine 6-SMT excretion in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances.

Establish the concentration-time profile of saliva melatonin concentrations and 24 hour 6-SMT urine excretion after 2 and 10 mg Circadin® mini-tablets single dose administration in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances.

Evaluate the adverse event profile after a single dose of 2 or 10 mg Circadin® mini-tablets in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances.

Open Label, Single Ascending Dose, Cross-over Study to Assess the Pharmacokinetics of Circadin® (Prolonged-Release Melatonin) Mini Tablets in Children With Neurodevelopmental Disorders and Sleep Disturbances

baseline profile of endogenous saliva melatonin concentrations and urine 6-SMT excretion [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]

To establish the 24 hour baseline profile of endogenous saliva melatonin concentrations and urine 6-SMT excretion in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances.

To establish the concentration-time profile of saliva melatonin concentrations and 24 hour 6-SMT urine excretion after 2 and 10 mg Circadin® mini-tablets single dose administration in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances.

adverse event profile after a single dose of 2 or 10 mg Circadin® mini-tablets [ Time Frame: up to 1 year ] [ Designated as safety issue: Yes ]

To evaluate the adverse event profile after a single dose of 2 or 10 mg Circadin® mini-tablets in children aged 2 up to and including 17 years with neurodevelopmental disorders with sleep disturbances.

Subject has a documented history of autistic spectrum disorder (ASD; as confirmed according to, DSM-IV-TR 299.00, 299.10 and 299.80 or ICD 10: F 84.0, F84.2, F84.3, F84.5, F84.9 ) or one of the following neurogenetic diseases according to ICD 10: Smith-Magenis syndrome, Angelman syndrome or Tuberous Sclerosis (Bourneville's disease)

Subject has current sleep problems; defined as difficulty initiating or maintaining sleep, or non restorative sleep, for at least 1 month (DSM-IV 307.42). Subject is able to comply with taking the study drug and collaborate freely with the study procedures;

Written informed consent from parents having parental responsibility or from the legal guardian(s). In the case of a child is aged 12 years or older the written informed consent of the child is needed in addition to that of parents having responsibility/legal guardian;

Subject is able to understand instructions in Dutch.

Exclusion Criteria:

Subject has history of difficulty with swallowing and/or easy choking;

Subject has current symptoms suggestive of obstructive sleep apnea syndrome or any breathing related sleep disorders or periodic limb movements;

Subject is unable to refrain from eating bananas and chocolate during the entire day before saliva collection;

Subject is unable to refrain from drinks containing artificial colorants, caffeine (including but not limited to coffee, tea, cola), or alcohol during the day of the collection;

Subject is unable to refrain from aspirin or drugs that contain ibuprofen on the collection day;

Participation in an investigational drug study within 90 days prior to the first dose and/or participation in more than 4 clinical trials in the last year. -

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01903681